Sirolimus, also known as rapamycin and marketed in the United States under the tradename RAPAMUNE® (Wyeth, Collegeville, Pa.), is currently indicated for the prevention of organ rejection after kidney transplant. Rapamycin derivatives useful for prevention of organ rejection have also been developed. For example, everolimus, marketed in the United States under the tradename CERTICAN® (Novartis, East Hanover, N.J.) is indicated for the prevention of organ rejection after heart or kidney transplantation.
Rapamycin has demonstrated anti-proliferative effects and has been shown to inhibit the progression of dermal Kaposi's sarcoma in patients with kidney transplants. S. DiPaolo, et al. Monitoring Antitumor Efficacy of Rapamycin in Kaposi Sarcoma, American Journal of Kidney Diseases, vol. 49, issue 3, 462-470. Rapamycin, in combination with doxorubicin, has been investigated for the treatment of melanoma. M. Romano, et al. Rapamycin inhibits doxorubicin-induced NF-kB/Rel nuclear activity and enhances the apoptosis of melanoma cells, European Journal of Cancer, vol. 40, issue 18, 2829-2836. Such data has prompted researchers to investigate the anti-proliferative potential of rapamycin and its derivatives. For example, temsirolimus, marketed in the United States under the tradename TORISEL® (Wyeth, Collegeville, Pa.), is currently indicated for the treatment of advanced renal cell carcinoma. Deforolimus is currently in Phase 2 clinical studies to evaluate deforolimus in patients with breast, endometrial, prostate cancer, and non-small cell lung cancer. While these rapamycin derivatives have demonstrated efficacy in treating some types of cancer, more research and development is needed to improve efficacy and response and survival rates.
Chloroquine is a 4-amino-substituted quinoline that has been used for over 60 years for malaria prophylaxis and treatment, rheumatoid arthritis treatment, and HIV treatment. Chloroquinoline derivatives such as hydroxylchloroquine are used to treat rheumatoid arthritis and systemic lupus erythematosis. Recent studies indicate that chloroquine may inhibit cell growth and may induce cell death in lung cancer cells. C. Fan, et al. Bioorg. Med. Chem. 2006 May 1; 14(9):3218-22. In 2006, researchers reported that adding chloroquine to standard chemotherapy and radiotherapy regimes for glioblastoma multiforme might improve survival rates of cancer patients receiving standard chemotherapy and radiotherapy. Annals of Internal Medicine, 7 Mar. 2006, vol. 144, issue 5, 1-31.
To date, there have been no reports of treating cancer in patients using a combination of a sirolimus drug and chloroquine or substituted quinoline.